Discovery of DS-9300: A Highly Potent, Selective, and Once-Daily Oral EP300/CBP Histone Acetyltransferase Inhibitor.
J Med Chem
; 66(1): 695-715, 2023 01 12.
Article
in En
| MEDLINE
| ID: mdl-36572866
ABSTRACT
Histone acetylation is a post-translational modification of histones that is catalyzed by histone acetyltransferases (HATs) and plays an essential role in cellular processes. The HAT domain of EP300/CBP has recently emerged as a potential drug target for cancer therapy. Here, we describe the identification of the novel, highly potent, and selective EP300/CBP HAT inhibitor DS-9300. Our optimization efforts using a structure-based drug design approach based on the cocrystal structures of the EP300 HAT domain in complex with compounds 2 and 3 led to the identification of compounds possessing low-nanomolar EP300 HAT inhibitory potency and the ability to inhibit cellular acetylation of histone H3K27. Optimization of the pharmacokinetic properties in this series resulted in compounds with excellent oral systemic exposure, and once-daily oral administration of 16 (DS-9300) demonstrated potent antitumor effects in a castrated VCaP xenograft mouse model without significant body weight loss.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Histones
/
Histone Acetyltransferases
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
J Med Chem
Journal subject:
QUIMICA
Year:
2023
Document type:
Article
Affiliation country:
Japan